TY - JOUR
T1 - Functional Proteomics Defines the Molecular Switch Underlying FGF Receptor Trafficking and Cellular Outputs
AU - Francavilla, Chiara
AU - Rigbolt, Kristoffer T.G.
AU - Emdal, Kristina B
AU - Carraro, Gianni
AU - Vernet, Erik
AU - Bekker-Jensen, Dorte B
AU - Streicher, Werner
AU - Wikström, Mats
AU - Sundström, Michael
AU - Bellusci, Saverio
AU - Cavallaro, Ugo
AU - Blagoev, Blagoy
AU - Olsen, Jesper V
N1 - Copyright © 2013 Elsevier Inc. All rights reserved.
PY - 2013/9/26
Y1 - 2013/9/26
N2 - The stimulation of fibroblast growth factor receptors (FGFRs) with distinct FGF ligands generates specific cellular responses. However, the mechanisms underlying this paradigm have remained elusive. Here, we show that FGF-7 stimulation leads to FGFR2b degradation and, ultimately, cell proliferation, whereas FGF-10 promotes receptor recycling and cell migration. By combining mass-spectrometry-based quantitative proteomics with fluorescence microscopy and biochemical methods, we find that FGF-10 specifically induces the rapid phosphorylation of tyrosine (Y) 734 on FGFR2b, which leads to PI3K and SH3BP4 recruitment. This complex is crucial for FGFR2b recycling and responses, given that FGF-10 stimulation of either FGFR2b_Y734F mutant- or SH3BP4-depleted cells switches the receptor endocytic route to degradation, resulting in decreased breast cancer cell migration and the inhibition of epithelial branching in mouse lung explants. Altogether, these results identify an intriguing ligand-dependent mechanism for the control of receptor fate and cellular outputs that may explain the pathogenic role of deregulated FGFR2b, thus offering therapeutic opportunities.
AB - The stimulation of fibroblast growth factor receptors (FGFRs) with distinct FGF ligands generates specific cellular responses. However, the mechanisms underlying this paradigm have remained elusive. Here, we show that FGF-7 stimulation leads to FGFR2b degradation and, ultimately, cell proliferation, whereas FGF-10 promotes receptor recycling and cell migration. By combining mass-spectrometry-based quantitative proteomics with fluorescence microscopy and biochemical methods, we find that FGF-10 specifically induces the rapid phosphorylation of tyrosine (Y) 734 on FGFR2b, which leads to PI3K and SH3BP4 recruitment. This complex is crucial for FGFR2b recycling and responses, given that FGF-10 stimulation of either FGFR2b_Y734F mutant- or SH3BP4-depleted cells switches the receptor endocytic route to degradation, resulting in decreased breast cancer cell migration and the inhibition of epithelial branching in mouse lung explants. Altogether, these results identify an intriguing ligand-dependent mechanism for the control of receptor fate and cellular outputs that may explain the pathogenic role of deregulated FGFR2b, thus offering therapeutic opportunities.
U2 - 10.1016/j.molcel.2013.08.002
DO - 10.1016/j.molcel.2013.08.002
M3 - Journal article
C2 - 24011590
VL - 51
SP - 707
EP - 722
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 6
ER -